EP1173209A1 - Compositions contraceptives contenant 2,1-benzisothiazoline 2,2-dioxydes et des progestatifs - Google Patents

Compositions contraceptives contenant 2,1-benzisothiazoline 2,2-dioxydes et des progestatifs

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Publication number
EP1173209A1
EP1173209A1 EP00928610A EP00928610A EP1173209A1 EP 1173209 A1 EP1173209 A1 EP 1173209A1 EP 00928610 A EP00928610 A EP 00928610A EP 00928610 A EP00928610 A EP 00928610A EP 1173209 A1 EP1173209 A1 EP 1173209A1
Authority
EP
European Patent Office
Prior art keywords
phase
daily dosage
alkyl
dosage units
daily
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00928610A
Other languages
German (de)
English (en)
Inventor
Gary S. Grubb
Lin Zhi
Todd K. Jones
Christopher M. Tegley
James P Edwards
Mark A. Collins
Valerie A. Mackner
Jay E Wrobel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth
Ligand Pharmaceuticals Inc
Original Assignee
Wyeth LLC
Ligand Pharmaceuticals Inc
American Home Products Corp
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Filing date
Publication date
Priority claimed from US09/552,038 external-priority patent/US6319912B1/en
Application filed by Wyeth LLC, Ligand Pharmaceuticals Inc, American Home Products Corp filed Critical Wyeth LLC
Publication of EP1173209A1 publication Critical patent/EP1173209A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone

Definitions

  • Intracellular receptors form a class of tr ⁇ t ⁇ rnll * y rrj ⁇ tnd gene regulators
  • the steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mmeralocorticoid receptor (MR)
  • PR progesterone receptor
  • ER estrogen receptor
  • AR antigen receptor
  • GR glucocorticoid receptor
  • MR mmeralocorticoid receptor
  • the natural hormone, or hgand, for the PR is the steroid progesterone, but
  • a compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound that inhibits the effect of the hormone is an antagonist
  • PR agonists Natural and synthetic are known to play an important role in the
  • PR agonists are used in birth control formulations, typically in the presence of an ER agonist ER agonists are used to treat the symptoms of menopause, but have been associated with a prohferative effect on the uterus that can lead to an increased risk of uterine cancers
  • Co-administration of a PR agonist reduces or ablates that ⁇ sk
  • PR antagonists may also be used m contraception In this context they may be administered alone (Ulmann et al, Ann N Y Acad Sci 261, 248, 1995), in combination with a PR agonist (Kekkonen et al, Fertility and Sterility 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 Al July 4, 1996)
  • PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz et al, Horm Cancer, 283, pub Birkhaeuser, Boston, Mass , ed Nedeckis) as well as uterine and ovarian cancers PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy et al, J Clin Endo Metab 76, 513, 1993) and endomet ⁇ osis (Kettel et al, Fertility and Sterility 56, 402, 1991)
  • PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (US 5719136)
  • PR antagonists such as mifep ⁇ stone and onap ⁇ stone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna et al, Ann N Y Acad Sci 761, 224, 1995)
  • Kamireddy et al disclosed a series of cyclic sulfonamides, e g , P and Q, useful for controlling undesired vegetation (WO 95/33746)
  • This invention provides combination therapies and dosing regimens utilizing antiprogestational agents in combination with one or more progestational agents
  • This invention further provides methods of treatment and dosing regimens further utilizing in combination with these antiprogestms and progestins, an estrogen, such as ethinyl estradiol
  • regimens and combinations may be administered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endomet ⁇ osis, polycystic ovary syndrome, carcinomas and adenocarcinomas of the endomet ⁇ um, ovary, breast, colon, prostate Additional uses of the invention include stimulation of food intake
  • the uses herein for the treatment and/or prevention of the conditions or diseases described above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effect dose or minimization of side effects or cyclic menstrual bleeding
  • the use of this invention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestm in combination with an estrogen or progestin or both These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cycle containing administration of no progestins, estrogens or anti-progestins
  • the progestins of these combinations may be administered alone or in combination with an estrogen for the first 14 to 24 days of the cycle, the progestins being administered at a dosage range equal in progestational activity to about 35 ⁇ g to about 150 ⁇ g levonorgestrel per day, preferably equal in activity to from about 35 ⁇ g to about 100 ⁇ g levonorgestrel per day
  • An antiprogestm may then be administered alone or in combination with an estrogen for a period of 1 to 1 1 days to begin on any cycle day between day 14 and 24
  • the anti-progestin in these combinations may be administered at a dose of from about 2 ⁇ g to about 50 ⁇ g per day and the estrogen may be administered at a dose of from about 10 ⁇ g to about 35 ⁇ g per day
  • a package or kit containing 28 tablets will include a placebo tablet on those days when the antiprogestm or progestin or estrogen is not administered
  • the progestins of this invention may be administered alone or in
  • the estrogen to be used in the combinations and formulations of this invention is preferably ethinyl estradiol
  • Progestational agents useful with this invention include, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, t ⁇ megestone, dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgest ⁇ mate
  • the preferred progestins for use in the combinations of this invention are levonorgestrel, gestodene and t ⁇ megestone
  • Examples of orally admimstered regimens of this invention over a 28 day cycle include administration of a progestational agent solely for the first 21 days at a daily dose equal in progestatonal activity to from about 35 to about 100 ⁇ g of levonorgestrel An antiprogestm compound of this invention may then be administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28 It is most preferred that the daily dosages of each relevant active ingredient be incorporated into a combined, single daily dosage unit, totaling 28 daily units per 28- day cycle
  • a progestational agent may be coadministered for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 150 ⁇ g levonorgestrel, preferably equal in activity to from about 35 to about 100 ⁇ g levonorgestrel, with an estrogen, such as ethmyl estradiol, at a daily dose range of from about 10 to about 35 ⁇ g
  • an antiprogestm administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28
  • Still another regimen within the scope of this invention will include coadmmistration from days 1 to 21 of a progestational agent, the progestational agent, preferably levonorgestrel, being administered at a daily dose equal m progestational activity to from about 35 to about 100 ⁇ g levonorgestrel, and an estrogen, such as ethmyl estradiol, at a daily dose
  • kits or packages of pharmaceutical formulations designed for use in the regimens described herein are preferably designed for daily oral admimstration over a 28-day cycle, preferably for one oral administration per day, and organized so as to indicate a single oral formulation or combination of oral formulations to be taken on each day of the 28-day cycle
  • each kit will include oral tablets to be taken on each the days specified, preferably one oral tablet will contam each of the combined daily dosages indicated
  • one 28-day kit may comprise a) an initial phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal in progestational activity to about 35 to about 100 ⁇ g levonorgestrel, b) a second phase of from 1 to 11 daily dosage units of an antiprogestm compound of this invention, each daily dosage unit containing an antiprogestm compound at a daily dosage of from about 2 to 50 mg, and c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle in which no antiprogestm, progestin or estrogen is administered
  • a preferred embodiment of this kit may comprise a) an initial phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal in progestational activity to about 35 to about 100 ⁇ g levonorgestrel. b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestm compound of this invention, each daily dosage unit containing an antiprogestm compound at a daily dosage of from about 2 to 50 mg, and c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28
  • Another 28-day cycle packaging regimen or kit of this invention comprises a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal in activity to from about 35 to about 100 ⁇ g levonorgestrel, and, as an estrogen, ethmyl estradiol at a daily dose range of from about 10 to about 35 ⁇ g, and b) a second phase of from 1 to 7 daily dosage units of an antiprogestm of this invention at a daily dose of from about 2 to 50 mg, and c) optionally, an orally and pharmaceutically acceptable placebo for each of the remammg 0 to 9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestm is administered
  • a preferred embodiment of the kit described above may comprise a) a first phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal in activity to from about 35 to about 100 ⁇ g levonorgestrel, and, as an estrogen, ethmyl estradiol at a daily dose range of from about 10 to about 35 ⁇ g, and b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestm administered at a daily dose of from about 2 to 50 mg, and c) optionally, a third phase of 4 daily dose units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28
  • a further 28-day packaged regimen or kit of this invention comprises a) a first phase of from 18 to 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal m activity to from about 35 to about 100 ⁇ g levonorgestrel, and ethmyl estradiol at a daily dose range of from about 10 to about 35 ⁇ g, b) a second phase of from 1 to 7 daily dose units, each daily dose unit containing an antiprogestm of this invention at a concentration of from 2 to 50 mg, and ethmyl estradiol at a concentration of from about 10 to about 35 ⁇ g, and c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0 to 9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestm is admimstered
  • a preferred embodiment of the package or kit just described comprises a) a first phase of 21 daily dosage units, each containing a progestational agent of this mvention at a daily dose equal in progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably from about 35 to about 100 ⁇ g levonorgestrel, and ethmyl estradiol at a daily dose range of from about 10 to about 35 ⁇ g, b) a second phase of 3 daily dose units for days 22 to 24, each dose unit containing an antiprogestm of this invention at a concentration of from 2 to 50 mg, and ethmyl estradiol at a concentration of from about 10 to about 35 ⁇ g, and c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28
  • kits In each of the regimens and kits just described, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed in each particular phase in which it is administered It is also understood that the daily dose units described are to be administered in the order described, with the first phase followed in order by the second and third phases To help facilitate compliance with each regimen, it is also preferred that the kits contain the placebo described for the final days of the cycle It is further preferred that each package or kit comprise a pharmaceutically acceptable package having indicators for each day of the 28-day cycle, such as a labeled blister package or dial dispenser packages known in the art
  • anti-progestational agents, anti-progestins and progesterone receptor antagonists are understood to be synonymous
  • progestins, progestational agents and progesterone receptor agonists are understood to refer to compounds of the same activity
  • dosage regimens may be adjusted to provide the optimal therapeutic response
  • several divided doses of each component may be administered daily or the dose may be proportionally increased or reduced as indicated by the exigencies of the therapeutic situation
  • reference to a daily dosage unit may also include divided units that are administered over the course of each day of the cycle contemplated Antiprogestm compounds which may be used in the kits, methods and regimens herein are those of the Formula 1
  • Ri and R 2 are each, independently, hydrogen, alky, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl, or Ri and R 2 are taken together form a ring and together contain -CH 2 (CH 2 ) n CH 2 - ,
  • Ri and R 2 are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a ey ⁇ -•ether bonded to the terminal end,
  • R is hydrogen, hydroxyl, NH 2 , alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, COR A , R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy. aminoalkyl, or substituted aminoalkyl, R 4 is hydrogen, halogen, -CN, -NH 2 , alkyl, substituted alkyl. alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl, R is a t ⁇ substituted phenyl ring having the structure,
  • X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O) 2 alkyl, aminoalkyl, substituted aminoalkyl, -N0 2 , perfluoroalkyl, 5 or 6 membered heterocychc ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B , -OCOR B , or -NR c COR B , R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl, R c is hydrogen, alkyl, or substituted alkyl,
  • Y and Z are each, independently, hydrogen, halogen, -CN, -N0 2 , alkoxy, alkyl, or thioalkyl, or R 5 is a five or six membered heteroaryl ring contaming 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO alkyl, alkoxy, aminoalkyl, COR D , and NR E COR D , R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy. substituted alkoxy, aminoalkyl, or substituted aminoalkyl, R E is hydrogen, alkyl, or substituted alkyl,
  • R 6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR 6 is bonded to a ring double bond, or pharmaceutically acceptable salt thereof
  • Preferred antiprogestm compounds for use with the methods and regimens this mvention are those having the structure
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 5 is a t ⁇ substituted phenyl rmg having the structure
  • X is halogen, OH, -CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl, S(0)alkyl, S(0) 2 alkyl, aminoalkyl, substituted aminoalkyl, -NO 2 , perfluoroalkyl, 5 or 6 membered heterocychc ring containing 1 to 3 heteroatoms, or thioalkoxy
  • Y and Z are each, independently, hydrogen, halogen, -CN, -N0 2 , alkoxy, alkyl, or thioalkyl, or R 5 is a five or six membered heteroaryl ring containing 1 , 2, or 3 heteroatoms selected from the group consisting of O, S, and NR 6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, N0 2 , alkyl, or alkoxy
  • R 6 is hydrogen, alkyl, alkoxy
  • R 3 is hydrogen
  • R is hydrogen
  • R 5 is a disubstituted phenyl ring having the structure
  • X is halogen, -CN, or -N0 ,
  • Y is hydrogen, halogen, -CN, -N0 2 , alkoxy, alkyl, or thioalkyl, or R is a five or six membered heteroaryl ring containing a heteroatom selected from the group consisting of O, S, and NR 6 with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, or NO 2 ,
  • R is hydrogen, or is absent when the nitrogen of NR 6 is bonded to a ⁇ ng double bond, or pharmaceutically acceptable salt thereof
  • the antiprogestm compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereoisomers While shown without respect to stereochemistry in Formula 1, the present invention includes such optical isomers and diastereoisomers, as well as the racemic and resolved, enantiome ⁇ cally pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof
  • alkyl is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms
  • alkenyl includes both straight- and branched-cham alkyl group of 2 to 6 carbon atoms containing at least one carbon-carbon double bond
  • alkynyl includes both straight- and branched-cham alkyl group of 2 to 6 carbon atoms with at least one carbon-carbon triple bond
  • substituted alkyl refers to alkyl, alkenyl, and alkynyl as containing one or more substituents from the group including halogen, CN, OH, NO 2 , ammo, aryl, heterocychc, substituted aryl, substituted heterocychc, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylammo, arylthio
  • substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment ⁇ onstitutes a stable chemical moiety
  • aryl is used herein to refer to an aromatic system of 6 to 14 carbon atoms, which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system
  • Preferred aryl groups include phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl groups
  • substituted aryl refers to aryl substituted by one or more substituents from the group including halogen, CN, OH, NO 2 , ammo, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylammo, or arylthio
  • heterocychc is used herein to describe a stable 4 to 14 membered monocyc c or multicyclic heterocychc ⁇ ng which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group mcludmg N, O, and S atoms
  • the N and S atoms may be oxidized, as an N-oxide, sulfoxide, or sulfone
  • the heterocychc ring also includes any multicyclic ring m which
  • substituted heterocychc is used herein to describe a heterocychc having one or more substituents selected from the group which includes halogen, CN, OH, NO 2 , ammo, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylammo, or arylthio
  • thioalkyl is used herein to refer to the SR group, where R is alkyl or substituted alkyl
  • alkoxy is used herein to refer to the OR group, where R is alkyl or substituted alkyl
  • aryloxy is used herein to refer to the OR group, where R is aryl or substituted aryl
  • alkylcarbonyl is used herein to refer to the RCO group, where R is alkyl or
  • salts can be formed of these antiprogestm compounds from organic and inorganic acids, for example, acetic, propiomc. lactic, citric, tarta ⁇ c, succimc, fuma ⁇ c, maleic, malonic, mandehc, malic, phthahc, hydrochloric, hydrobromic, phosphoric, nitric, sulfu ⁇ c, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfomc, camphorsulfonic, and similarly known acceptable acids
  • Salts may also be formed from inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, and organic bases, such as ammonium, mono-, di-, and t ⁇ methylammonium, mono-, di- and triethylammomum, mono-, di- and tripropylammonium (iso and normal), ethyl- dimethylam
  • antiprogestm compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures These schemes show the preparation of representative antiprogestm compounds of this invention
  • the protected sultam 7 next is treated with a strong organo-metallic base (e g , butyl lithium, lithium dnsopropylamide, potassium hexamethyldisilylazide) in an inert solvent (e g , THF, diethyl ether) under nitrogen at reduced temperature (ca -20°C) (Kende et al, Synth Commun 12, 1, 1982)
  • a strong organo-metallic base e g , butyl lithium, lithium dnsopropylamide, potassium hexamethyldisilylazide
  • an inert solvent e g , THF, diethyl ether
  • excess electrophile such as an alkyl ha de, preferably the iodide
  • the electrophile should be bifunctional, I e , a dnodide
  • brommation of the sultam 8 proceeds regioselectively at room temperature with bromme in acetic acid (
  • the bromide 9 then is reacted with a palladium salt (e g , tetrak ⁇ s(t ⁇ phenylphosh ⁇ ne)pallad ⁇ um(0)), in a suitable solvent (e g , THF, dimethoxyethane, ethanol, toluene) under an inert atmosphere (argon, nitrogen)
  • a suitable solvent e g , THF, dimethoxyethane, ethanol, toluene
  • an inert atmosphere argon, nitrogen
  • the mixture then is treated with an arylboronic acid or arylboronic acid ester and a base (sodium carbonate, t ⁇ ethylamme, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions at elevated temperature to give the biphenyl sultam 10
  • the protecting group is removed under appropriate conditions and the final product 11 is isolated and purified by standard means
  • R X leaving group, e g , iodide
  • the resultant mono-alkylated compound may be then isolated and re- subjected to the reaction conditions using R -X, or alternativel y , used in situ for the second alkylation with R -X
  • Scheme 2 Other methodologies also are available for coupling the aryl group, Ar, to the sultam platform for example, reaction of the bromide 9 with an aryl stannane, aryl zinc, or aryl magnesium ha de in the presence of a palladium or nickel catalyst (Scheme 2)
  • the required aryl-metallic species are formed via standard techniques
  • the bromide 9 may be converted to an aryl boronic acid via standard procedures (treatment with n-butylhthium followed by addition of t ⁇ methyl borate and subsequent boronic ester hydrolysis) that will then undergo the range of previously described coupling procedures with a suitable aryl bromide
  • the antiprogestational activity of the compounds of this invention was demonstrated in an in vitro standard pharmacological test procedure which evaluated the antiprogestational potency of a representative compound of this invention by measuring its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids
  • the compound of Example 1 had an IC50 of 900 nM
  • the IC50 is the concentration of test compound that gives half-maximal decrease in 3 nM progesterone induced PRE-luciferase activity
  • the results obtamed in this standard pharmacological test procedure demonstrate that the compounds of this invention are progestational antagonists, and are therefore useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combined with an estrogen), in the treatment of endomet ⁇ osis, luteal phase defects, benign breast and prostatic diseases and prostate, breast, ovarian, uterine and endomet ⁇ al cancers
  • the antiprogestm compounds of this invention can be used alone as a sole therapeutic agent or can be used in combination with other agents, such as other estrogens, progestins, or androgens
  • the antiprogestational compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice
  • the pharmaceutical carrier may be solid or liquid
  • a solid carrier can include one or more substances which may also act as flavo ⁇ ng agents, lubricants, solubi zers, suspending agents, fillers, ghdants, compression aids, binders or tablet-disintegrating agents, it can also be an encapsulating material
  • the carrier is a finely divided solid that is in admixture with the finely divided active ingredient
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired
  • the powders and tablets preferably contain up to 99% of the active ingredient
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrohdme, low melting waxes and ion exchange resins Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs
  • Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized by, for example, intramuscular, lntrape ⁇ toneal or subcutaneous injection Sterile solutions can also be administered intravenously
  • Sterile solutions can also be administered intravenously
  • the compounds of this invention can also be administered orally either in liquid or solid composition form
  • the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository
  • the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices
  • the creams and ointments may be viscous liquid or semisohd emulsions of either the oil-in-water or water-m-oil type Pastes comprised of absorptive powders dispersed in petroleum or hydrophihc petroleum containing the active ingredient may also
  • the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0 02 ⁇ g/kg - 750 ⁇ g/kg Treatment will generally be initiated with small dosages less than the optimum dose of the compound Thereafter the dosage is increased until the optimum effect under the circumstances is reached, precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated
  • the pharmaceutical composition is in unit dosage form, e g as tablets or capsules
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient
  • the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled synnges or sachets containing liquids
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in
  • DMEM BioWhittaker
  • fetal bovine serum heat inactivated
  • 0 1 mM MEM non-essential ammo acids 0 1 mM MEM non-essential ammo acids
  • lOOU/ml penicillin lOOmg/ml streptomycin
  • 2 mM GlutaMax GIBCO, BRL
  • Example 1 had an IC 50 of 900 nM The IC 50 is the concentration of test compound that gives half-maximal decrease in 3 nM progesterone induced PRE-luciferase activity

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Abstract

Cette invention a trait à des thérapies de combinaison cyclique utilisant, en combinaison avec une progestérone, un oestrogène, ou les deux, des antagonistes du récepteur de la progestérone correspondant à la structure (1) ou leur sel admissible du point de vue pharmaceutique. Dans cette structure les substituants sont tels que définis dans le descriptif.
EP00928610A 1999-05-04 2000-05-01 Compositions contraceptives contenant 2,1-benzisothiazoline 2,2-dioxydes et des progestatifs Withdrawn EP1173209A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US18302399P 1999-05-04 1999-05-04
US183023P 1999-05-04
US552038 2000-04-19
US09/552,038 US6319912B1 (en) 1999-05-04 2000-04-19 Cyclic regimens using 2,1-benzisothiazoline 2,2-dioxides
PCT/US2000/011642 WO2000066163A1 (fr) 1999-05-04 2000-05-01 Compositions contraceptives contenant 2,1-benzisothiazoline 2,2-dioxydes et des progestatifs

Publications (1)

Publication Number Publication Date
EP1173209A1 true EP1173209A1 (fr) 2002-01-23

Family

ID=26878663

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00928610A Withdrawn EP1173209A1 (fr) 1999-05-04 2000-05-01 Compositions contraceptives contenant 2,1-benzisothiazoline 2,2-dioxydes et des progestatifs

Country Status (6)

Country Link
EP (1) EP1173209A1 (fr)
JP (1) JP2002543154A (fr)
CN (1) CN1349414A (fr)
AU (1) AU4681900A (fr)
CA (1) CA2372586A1 (fr)
MX (1) MXPA01011289A (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0066163A1 *

Also Published As

Publication number Publication date
AU4681900A (en) 2000-11-17
CA2372586A1 (fr) 2000-11-09
JP2002543154A (ja) 2002-12-17
MXPA01011289A (es) 2003-07-14
CN1349414A (zh) 2002-05-15

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